Targeted Therapies: Trastuzumab and Beyond

Only trastuzumab, an anti-HER2 antibody, has been approved for gastroesophageal cancers, but several others are in development. Johanna Bendell, MD, of the Sarah Cannon Research Institute in Nashville, TN, reviewed the promise of targeted therapies designed to block HER2 or each of several other molecular pathways.8

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“We are only at the start of finding effective targeted agents for patients with gastroesophageal cancers,” noted Dr. Bendell. “We continue to identify new pathways and agents that may work either alone, in combination with chemotherapy, or in combination with other targeted agents. We have also seen that with these targeted agents the individual patient’s tumor matters, from the epidemiology of the tumor to biomarker-positive subpopulations who will likely receive the most benefit.”8

HER2 inhibition was the earliest pathway developed for targeted therapy in esophageal and esophagogastric cancers. Trastuzumab has been approved for use with cisplatin and 5-FU as a first-line therapy of HER2-overexpressing tumors situated in the stomach or the gastroesophageal junction.8 Other molecular pathway inhibitors are in various stages of development, but have not yet been approved as treatments for these cancers. Lapatinib, another HER2 (and HER1) inhibitor, is being studied in the randomized phase 3 LOGiC study of gastric, esophageal, and gastroesophageal cancers, comparing outcomes among patients administered capecitabine plus oxaliplatin either with or without lapatinib, Dr. Bendell noted.8

HER2 testing is now routinely employed to identify patients who are candidates for HER2-targeted (trastuzumab) therapy. In the largest study of HER2 testing published to date, researchers at the Mayo Clinic in Rochester, MN, found that patients with esophageal adenocarcinoma should be initially screened for HER2 using immunohistochemistry (IHC) rather than fluorescence in situ hybridization (FISH); FISH is only warranted when IHC test results are indeterminate.9

Dr. Bendell also reviewed the status of therapies targeting the EGFR, mTOR, and c-met pathways, noting disappointing results for the EGFR inhibitor panitumumab in gastroesophageal adenocarcinomas (with worse OS for patients receiving panitumumab in the REAL3 clinical trial) and the mTOR inhibitor everolimus for patients with metastatic gastric or gastroesophageal tumors.8 (Despite the absence of an overall survival advantage, however, progression-free survival [PFS] appears to be superior among patients administered everolimus: 1.7 vs. 1.4 months; HR, 0.66; 95% CI: 0.56-0.78, Dr. Bendell noted.8)

On the other hand, c-MET represents a “promising” additional pathway under investigation for targeted inhibition as a treatment for metastatic gastroesophageal cancer, Dr. Bendell reported.8

“Activation of the c-met pathway leads to cellular survival, proliferation, invasion, and motility,” Dr. Bendell noted. “Upregulation of the c-met pathway is seen in gastroesophageal cancers.”8